This invention relates to a process for the preparation of benzimidazole derivatives and pharmaceutically acceptable salts thereof exhibiting excellent hypoglycemic action and intermediates for their synthesis.
Some benzimidazole derivatives having hypoglycemic activity and pharmaceutically acceptable salts thereof and a process for the preparation of these derivatives are disclosed in Japanese Patent Application Publication Hei-9-295970 (European Patent Application Publication number 00745600 and U.S. Pat. No. 5,886,014).
The known method for the preparation of the benzimidazole derivatives comprises:
1) protection of the amino group of a nitroaniline derivative, 
(wherein A is an amino protecting group, R is methoxy and the like);
2) a few reactions via the amino-protected nitroaniline derivative to afford an N-methyl-1,2-phenylenediamine derivative, and
3) reaction of the N-methyl-1,2-phenylenediamine derivative by heating with a methoxycarbonylmethyloxybenzylthiazolidinone derivative in the presence of an acid to produce a benzimidazole derivative shown below. 
(wherein R is methoxy and the like)
In the method disclosed in Japanese Patent Application Publication Hei-9-295970 (U.S. Pat. No. 5,886,014), the overall yields of the benzimidazole derivatives, especially the two reactions shown above, are low and this method can not practically be used. A practical large scale method for the synthesis of the benzimidazole derivatives is needed, in which method the product is of good purity and is obtained by easy procedures using cheap starting materials, and in good yield.
We made many efforts in order to find a good synthetic method for a large scale preparation of the benzimidazole derivatives for a long time. We found a good method for the preparation which comprises the reaction of a group of carboxylic acid derivatives with a group of optionally protected amine derivatives.
This invention provides a process for the preparation of the benzimidazole derivatives exhibiting excellent hypoglycemic action or a pharmaceutically acceptable salt thereof and their important synthetic intermediates.
This invention is directed to synthetic intermediates of formulae [1], [2] and [3] and processes for preparation illustrated in [4] and [5].
[1] A compound of formula (1) (which is referred to as compound (1) hereinafter) or a pharmaceutically acceptable salt thereof, 
(wherein R1a, R2a, R3a and R4a are each independently hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, benzyloxy, acetoxy, trifluoromethyl or halogen, and R5a and R6a are each independently an amino protecting group).
Preferable compounds of formula (1) are:
[1-1] compounds and pharmaceutically acceptable salts thereof according to [1] wherein R5a and R6a are each independently t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl;
[1-2] compounds and pharmaceutically acceptable salts thereof according to [1] wherein R5a and R6a are each t-butoxycarbonyl;
[1-3] compounds and pharmaceutically acceptable salts thereof according to any one of [1], [1-1] or [1-2] wherein R1a, R2a, R3a and R4a are each independently hydrogen or C1-C4 alkoxy;
[1-4] compounds and pharmaceutically acceptable salts thereof according to any one of [1], [1-1] or [1-2] wherein R1a, R2a, R3a and R4a are each independently hydrogen or methoxy; and
[1-5] compounds and pharmaceutically acceptable salts thereof according to [1] wherein R1a, R2a and R4a are each hydrogen, R3a is methoxy, and R5a and R6a are each t-butoxycarbonyl.
The C1-C6 alkyl group of compound (1) is a C1-C6 straight or branched chain alkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl, preferably C1-C4 alkyl, more preferably methyl or ethyl and most preferably methyl.
The C1-C6 alkoxyl group of compound (1) is a C1-C6 alkyl described above group attached to an oxygen atom, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, 1-ethylpropoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy or 2-ethylbutoxy, preferably C1-C4 alkoxy, more preferably methoxy or ethoxy and most preferably methoxy.
The halogen atom of compound (1) is, for example, fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
The amino protecting group in the definition of compound (1) is, for example, t-butoxycarbonyl; trityl; (C6-C10)aryl-methyl, which is optionally substituted with C1-C6 alkyl, C1-C6 alkoxy or halogen, such as benzyl, methylbenzyl, methoxybenzyl, chlorobenzyl, bromobenzyl and naphthylmethyl; or (C6-C10)aryl-methyloxycarbonyl, which is optionally substituted with C1-C6 alkyl, C1-C6 alkoxy or halogen, such as benzyloxycarbonyl, methylbenzyloxycarbonyl, methoxybenzyloxycarbonyl, chlorobenzyloxycarbonyl, bromobenzyloxycarbonyl and naphthylmethyloxycarbonyl. t-Butoxycarbonyl, benzyl, p-methoxybenzyl, p-bromobenzyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl and p-bromobenzyloxycarbonyl are preferred; t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl and p-bromobenzyloxycarbonyl are more preferred and t-butoxycarbonyl is particularly preferred.
In compound (1), preferably R1a, R2a, R3a and R4a are each independently hydrogen or C1-C4 alkoxy; more preferably R1a, R2a, R3a and R4a are each independently hydrogen or methoxy; and most preferably R1a, R2a and R4a are each hydrogen and most preferably R3a is methoxy; and preferably R5a and R6a are each independently t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl and more preferably R5a and R6a are each t-butoxycarbonyl.
Pharmaceutically acceptable salts in the definition of salts of compound (1) are, for example, hydrohalogenides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide; perchlorates; sulfates; phosphates; carbonates; C1-C6 alkylsulfonates, which are optionally substituted with fluorines, such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, pentafluoroethanesulfonate, propanesulfonate, butanesulfonate, pentanesulfonate and hexanesulfonate; C6-C10 arylsulfonates such as benzenesulfonate and p-toluenesulfonate; carboxylic acid salts such as acetate, propionate, butyrate, benzoate, fumarate, maleate, succinate, citrate, tartarate, oxalate and malonate; and amino acid addition salts such as glutamate and aspartate. Hydrochlorides, sulfates, and carboxylic acid salts are more preferred, and hydrochlorides are particularly preferred. The pharmaceutically acceptable salts of this invention include hydrates and solvates of organic solvents.
Typical compounds of formula (1) are exemplified in the Tables 1 to 4. Throughout the tables the following abbreviations are used with the following meaning:
Exp. Comp. No: Exemplification compound number
Me: methyl, Et: ethyl, Pr: propyl, iPr: isopropyl, Bu: butyl, iBu: isobutyl, sBu: secondary butyl, tBu: tertiary butyl, Bz: benzyl, Ac: acetyl, Boc: tertiary butoxycarbonyl, Z: benzyloxycarbonyl, Moz: p-methoxybenzyloxycarbonyl, 4BrZ: p-bromobenzyloxycarbonyl
Preferable exemplification compounds in the tables are those having exemplification compound numbers 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-36, 1-37, 1-38, 1-39, 1-40, 1-41, 1-42, 1-43, 1-44, 2-1, 2-2, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 2-11, 2-36, 2-37, 2-38, 2-39, 2-40, 2-41, 2-42, 2-43, 2-44, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 3-11, 3-36, 3-37, 3-38, 3-39, 3-40, 3-41, 3-42, 3-43, 3-44, 4-1, 4-2, 4-3, 4-4, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 4-11, 4-36, 4-37, 4-38, 4-39, 4-40, 4-41, 4-42, 4-43 and 4-44; more preferably 1-1, 1-2, and 1-36; most preferably 1-2, which is N,N-di-tertiary butoxycarbonyl-2-nitro-5-methoxyaniline.
[2] A compound of formula (2) (which is referred to as compound (2) hereinafter) or a pharmaceutically acceptable salt thereof, 
(wherein R1b, R2b, R3b and R4b are each independently hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, benzyloxy, acetoxy, trifluoromethyl or halogen, R7b is C1-C6 alkyl and R8b is an amino protecting group).
Preferable compounds of formula (2) are:
[2-1] compounds and pharmaceutically acceptable salts thereof according to [2] wherein R8b is t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl;
[2-2] compounds and pharmaceutically acceptable salts thereof according to [2] wherein R8b is t-butoxycarbonyl;
[2-3] compounds and pharmaceutically acceptable salts thereof according to any one of [2], [2-1] or [2-2] wherein R7b is C1-C4 alkyl;
[2-4] compounds and pharmaceutically acceptable salts thereof according to any one of [2], [2-1] or [2-2] wherein R7b is C1-C2 alkyl;
[2-5] compounds and pharmaceutically acceptable salts thereof according to any one of [2], [2-1] or [2-2] wherein R7b is methyl;
[2-6] compounds and pharmaceutically acceptable salts thereof according to any one of [2], [2-1], [2-2], [2-3], [2-4] or [2-5] wherein R1b, R2b, R3b and R4b are each independently hydrogen or C1-C4 alkoxy;
[2-7] compounds and pharmaceutically acceptable salts thereof according to any one of [2], [2-1], [2-2], [2-3], [2-4] or [2-5] wherein R1b, R2b, R3b and R4b are each independently hydrogen or methoxy; and
[2-8] compounds and pharmaceutically acceptable salts thereof according to [2] wherein R1b, R2b and R4b are each hydrogen, R3b is methoxy, R7b is methyl and R8b is t-butoxycarbonyl.
The C1-C6 alkyl group of compound (2) is as defined in [1], preferably C1-C4 alkyl, more preferably methyl or ethyl and most preferably methyl. The C1-C6 alkoxyl group of compound (2) is as defined in [1], preferably C1-C4 alkoxyl, more preferably methoxy or ethoxy and most preferably methoxy. The halogen atom of compound (2) is as defined in [1], preferably fluorine, chlorine or bromine.
The amino protecting group of compound (2) is as defined in [1], preferably t-butoxycarbonyl, benzyl, p-methoxybenzyl, p-bromobenzyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl; more preferably t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl; most preferably t-butoxycarbonyl.
In compound (2), preferably R1b, R2b, R3b and R4b are each independently hydrogen or C1-C4 alkoxy; more preferably R1b, R2b, R3b and R4b are each independently hydrogen or methoxy; most preferably R1b, R2b and R4b are each hydrogen and most preferably R3b is methoxy,
preferably R7b is C1-C4 alkyl; more preferably C1-C2 alkyl and most preferably methyl, and
preferably R8b is t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl; more preferably R8b is t-butoxycarbonyl.
Pharmaceutically acceptable salts of compound (2) are as defined in [1].
Typical compounds (2) are exemplified in Tables 5 to 8. Throughout the tables the following abbreviations are used with the following meaning:
Exp. Comp. No: Exemplification compound number
Me: methyl, Et: ethyl, Pr: propyl, iPr: isopropyl, Bu: butyl, iBu: isobutyl, sBu: secondary butyl, tBu: tertiary butyl, Bz: benzyl, Ac: acetyl, Boc: tertiary butoxycarbonyl, Z: benzyloxycarbonyl, Moz: p-methoxybenzyloxycarbonyl, 4BrZ: p-bromobenzyloxycarbonyl
Preferable exemplification compounds in the tables are those having exemplification compound numbers 5-2, 5-3, 5-4, 5-5, 5-6, 5-8, 5-9, 5-10, 5-11, 5-12, 5-13, 5-14, 5-15, 5-16, 5-17, 5-18, 5-19, 5-20, 5-46, 5-47, 5-48, 5-49, 5-50, 5-51, 5-52, 5-53, 5-54, 5-55, 5-56, 5-57, 5-58, 6-2, 6-3, 6-4, 6-5, 6-6, 6-8, 6-9, 6-10, 6-11, 6-12, 6-13, 6-14, 6-15, 6-16, 6-17, 6-18, 6-19, 6-20, 6-46, 6-47, 6-48, 6-49, 6-50, 6-51, 6-52, 6-53, 6-54, 6-55, 6-56, 6-57, 6-58, 7-2, 7-3, 7-4, 7-5, 7-6, 7-8, 7-9, 7-10, 7-11, 7-12, 7-13, 7-14, 7-15, 7-16, 7-17, 7-18, 7-19, 7-20, 7-46, 7-47, 7-48, 7-49, 7-50, 7-51, 7-52, 7-53, 7-54, 7-55, 7-56, 7-57, 7-58, 8-2, 8-3, 8-4, 8-5, 8-6, 8-8, 8-9, 8-10, 8-11, 8-12, 8-13, 8-14, 8-15, 8-16, 8-17, 8-18, 8-19, 8-20, 8-46, 8-47, 8-48, 8-49, 8-50, 8-51, 8-52, 8-53, 8-54, 8-55, 8-56, 8-57 and 8-58; more preferably 5-8, 5-9, 5-46 and 5-47; most preferably 5-8, which is N-methyl-N-tert-butoxycarbonyl-2-amino-5-methoxyaniline.
[3] A compound of formula (3) (which is referred to as compound (3) hereinafter) or a pharmaceutically acceptable salt thereof, 
(wherein R1c, R2c, R3c and R4c are each independently hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, benzyloxy, acetoxy, trifluoromethyl or halogen, R7c is C1-C6 alkyl and R8c is hydrogen or an amino protecting group).
Preferable compounds (3) are:
[3-1] compounds and pharmaceutically acceptable salts thereof according to [3] wherein R8c is hydrogen, t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl;
[3-2] compounds and pharmaceutically acceptable salts thereof according to [3] wherein R8c is hydrogen or t-butoxycarbonyl;
[3-3] compounds and pharmaceutically acceptable salts thereof according to [3] wherein R8c is t-butoxycarbonyl;
[3-4] compounds and pharmaceutically acceptable salts thereof according to any one of [3], [3-1], [3-2] or [3-3] wherein R7c is C1-C4 alkyl;
[3-5] compounds and pharmaceutically acceptable salts thereof according to any one of [3], [3-1], [3-2] or [3-3] wherein R7c is C1-C2 alkyl;
[3-6] compounds and pharmaceutically acceptable salts thereof according to any one of [3], [3-1], [3-2] or [3-3] wherein R7c is methyl;
[3-7] compounds and pharmaceutically acceptable salts thereof according to any one of [3], [3-1], [3-2], [3-3], [3-4], [3-5] or [3-6] wherein R1c, R2c, R3c and R4c are each independently hydrogen or C1-C4 alkoxy;
[3-8] compounds and pharmaceutically acceptable salts thereof according to any one of [3], [3-1], [3-2], [3-3], [3-4], [3-5] or [3-6] wherein R1c, R2c, R3c and R4c are each independently hydrogen or methoxy; and
[3-9] compounds and pharmaceutically acceptable salts thereof according to [3] wherein R1c, R2c and R4c are each hydrogen, R3c is methoxy, R7c is methyl and R8c is t-butoxycarbonyl.
The C1-C6 alkyl group of compound (3) is as defined in [1]; preferably C1-C4 alkyl; more preferably methyl or ethyl and most preferably methyl.
The C1-C6 alkoxyl group of compound (3) is as defined in [1]; preferably C1-C4 alkoxy; more preferably methoxy or ethoxy and most preferably methoxy.
The halogen atom of compound (3) is as defined in [1], preferably fluorine, chlorine or bromine.
The amino protecting group of compound (3) is as defined in [1], preferably t-butoxycarbonyl, benzyl, p-methoxybenzyl, p-bromobenzyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl; more preferably t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl; most preferably t-butoxycarbonyl.
In compound (3), preferably R1c, R2c, R3c and R4c are each independently hydrogen or C1-C4 alkoxy; more preferably R1c, R2c, R3c and R4c are each independently hydrogen or methoxy; most preferably R1c R2c and R4c are each hydrogen and most preferably R3c is methoxy; and preferably R7c is C1-C4 alkyl; more preferably C1-C2 alkyl and most preferably methyl.
preferably R8c is hydrogen, t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl; more preferably R8c is hydrogen or t-butoxycarbonyl; most preferably R8c is t-butoxycarbonyl.
Pharmaceutically acceptable salts of the compound (3) are as defined in [1]. Typical compounds (3) are exemplified in Tables 9 to 13. Throughout the tables the following abbreviations are used with the following meaning:
Exp. Comp. No: Exemplification compound number
Me: methyl, Et: ethyl, Pr: propyl, iPr: isopropyl, Bu: butyl, iBu: isobutyl, sBu: secondary butyl, tBu: tertiary butyl, Bz: benzyl, Ac: acetyl, Boc: tertiary butoxycarbonyl, Z: benzyloxycarbonyl, Moz: p-methoxybenzyloxycarbonyl, 4BrZ: p-bromobenzyloxycarbonyl
Preferable exemplification compounds in the tables are those having exemplification compound numbers 9-2, 9-3, 9-4, 9-5, 9-6, 9-8, 9-9, 9-10, 9-11, 9-12, 9-13, 9-14, 9-15, 9-16, 9-17, 9-18, 9-19, 9-20, 9-46, 9-47, 9-48, 9-49, 9-50, 9-51, 9-52, 9-53, 9-54, 9-55, 9-56, 9-57, 9-58, 10-2, 10-3, 10-4, 10-5, 10-6, 10-8, 10-9, 10-10, 10-11, 10-12, 10-13, 10-14, 10-15, 10-16, 10-17, 10-18, 10-19, 10-20, 10-46, 10-47, 10-48, 10-49, 10-50, 10-51, 10-52, 10-53, 10-54, 10-55, 10-56, 10-57, 10-58, 11-2, 11-3, 11-4, 11-5, 11-6, 11-8, 11-9, 11-10, 11-11, 11-12, 11-13, 11-14, 11-15, 11-16, 11-17, 11-18, 11-19, 11-20, 11-46, 11-47, 11-48, 11-49, 11-50, 11-51, 11-52, 11-53, 11-54, 11-55, 11-56, 11-57, 11-58, 12-2, 12-3, 12-4, 12-5, 12-6, 12-8, 12-9, 12-10, 12-11, 12-12, 12-13, 12-14, 12-15, 12-16, 12-17, 12-18, 12-19, 12-20, 12-46, 12-47, 12-48, 12-49, 12-50, 12-51, 12-52, 12-53, 12-54, 12-55, 12-56, 12-57, 12-58, 13-2, 13-3, 13-4, 13-5, 13-6, 13-8, 13-9, 13-10, 13-11, 13-12, 13-13, 13-14, 13-15, 13-16, 13-17, 13-18, 13-19, 13-20, 13-46, 13-47, 13-48, 13-49, 13-50, 13-51, 13-52, 13-53, 13-54, 13-55, 13-56, 13-57 and 13-58,; more preferably 9-8, 9-9, 9-46, 9-47, 13-8, 13-9, 13-46 or 13-47; most preferably 9-8, which is N-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-methoxyphenyl]-N-methylcarbamic acid t-butyl ester.
[4] A process for the preparation of a compound of formula (5) (which is referred to as compound (5) hereinafter) or a pharmaceutically acceptable salt thereof by a reaction of a compound of formula (4) (which is referred to as compound (4) hereinafter) with alkali metal alkoxide, 
wherein R1d, R2d, R3d and R4d are each independently hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, benzyloxy, acetoxy, trifluoromethyl or halogen, and R5d and R6d are each an amino protecting group. 
wherein R1d, R2d, R3d, R4d, and R5d are as defined above.
In the process for preparation described above, preferable processes are:
[4-1] a process for the preparation of a compound or a pharmaceutically acceptable salt thereof according to [4] wherein R5d and R6d are each t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl;
[4-2] a process for the preparation of a compound or a pharmaceutically acceptable salt thereof according to [4] wherein R5d and R6d are each t-butoxycarbonyl;
[4-3] a process for the preparation of a compound or a pharmaceutically acceptable salt thereof according to any one of [4], [4-1] or [4-2] wherein R1d, R2d, R3d and R4d are each independently hydrogen or C1-C4 alkoxy;
[4-4] a process for the preparation of a compound or a pharmaceutically acceptable salt thereof according to any one of [4], [4-1] or [4-2] wherein R1d, R2d, R3d and R4d are each independently hydrogen or methoxy; and
[4-5] a process for the preparation of a compound or a pharmaceutically acceptable salt thereof according to [4] wherein R1d, R2d and R4d are each hydrogen, R3d is methoxy, and R5d and R6d are each t-butoxycarbonyl.
The C1-C6 alkyl group of compounds (4) and (5) is as defined in [1], preferably the alkyl group is C1-C4 alkyl, more preferably the alkyl group is methyl or ethyl and most preferably the alkyl group is methyl.
The C1-C6 alkoxy group of compounds (4) and (5) is as defined in [1], preferably the alkoxy group is C1-C4 alkoxy, more preferably the alkoxy group is methoxy or ethoxy and most preferably the alkoxy is methoxy.
The halogen atom of compounds (4) and (5) is defined as in [1], preferably the halogen atom is fluorine, chlorine or bromine.
The amino protecting group of compounds (4) and (5) is as defined in [1], preferably the protecting group is t-butoxycarbonyl, benzyl, p-methoxybenzyl, p-bromobenzyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl, more preferably one is t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl, most preferably one is t-butoxycarbonyl.
In compounds (4) and (5), preferably R1d, R2d, R3d and R4d are each independently hydrogen or C1-C4 alkoxy; more preferably R1d, R2d, R3d and R4d are each independently hydrogen or methoxy; most preferably R1d, R2d and R4d are each hydrogen and most preferably R3d is methoxy.
In compound (4), preferably R5d and R6d are each independently t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl; more preferably R5d and R6d are each t-butoxycarbonyl.
In compound (5), preferably R5d is t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl; more preferably R5d is t-butoxycarbonyl.
Pharmaceutically acceptable salts of compound (5) are as defined in [1].
[5] A process for the preparation of a benzimidazole derivative of formula (9) (which is referred to as compound (9) hereinafter) or a pharmaceutically acceptable salt thereof by condensation of a compound of formula (6) (which is referred to as compound (6) hereinafter) with a compound of formula (7) (which is referred to as compound (7) hereinafter) in the presence of a condensing agent to afford a compound of formula (8) (which is referred to as compound (8) hereinafter), followed by, if necessary removal of the amino protecting group of compound (8), and then cyclization of compound (8) in the presence of an acid, 
wherein R1e, R2e, R3e and R4e are each independently hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, benzyloxy, acetoxy, trifluoromethyl or halogen, R7e is C1-C6 alkyl and R8e is hydrogen or an amino protecting group, 
wherein R1e, R2e, R3e, R4e, R7e and R8e are as defined above 
wherein R1e, R2e, R3e, R4e, and R7e are as defined above.
In the process for preparation described above, preferable processes are:
[5-1] a process for the preparation of a benzimidazole derivative or a pharmaceutically acceptable salt thereof according to [5] wherein R8e is hydrogen, t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl;
[5-2] a process for the preparation of a benzimidazole derivative or a pharmaceutically acceptable salt thereof according to [5] wherein R8e is hydrogen or t-butoxycarbonyl;
[5-3] a process for the preparation of a benzimidazole derivative or a pharmaceutically acceptable salt thereof according to [5] wherein R8e is t-butoxycarbonyl;
[5-4] a process for the preparation of a benzimidazole derivative or a pharmaceutically acceptable salt thereof according to any one of [5], [5-1], [5-2] or [5-3] wherein R7e is C1-C4 alkyl;
[5-5] a process for the preparation of a benzimidazole derivative or a pharmaceutically acceptable salt thereof according to any one of [5], [5-1], [5-2] or [5-3] wherein R7e is C1-C2 alkyl;
[5-6] a process for the preparation of a benzimidazole derivative or a pharmaceutically acceptable salt thereof according to any one of [5], [5-1], [5-2] or [5-3] wherein R7e is methyl;
[5-7] a process for the preparation of a benzimidazole derivative or a pharmaceutically acceptable salt thereof according to any one of [5], [5-1], [5-2], [5-3], [5-4], [5-5] or [5-6] wherein R1e, R2e, R3e and R4e are each independently hydrogen or C1-C4 alkoxy;
[5-8] a process for the preparation of a benzimidazole derivative or a pharmaceutically acceptable salt thereof according to any one of [5], [5-1], [5-2], [5-3], [5-4], [5-5] or [5-6] R1e, R2e, R3e and R4e are each independently hydrogen or methoxy; and
[5-9] a process for the preparation of a benzimidazole derivative or a pharmaceutically acceptable salt thereof according to [5] wherein R1e, R2e and R4e are each hydrogen, R3e is methoxy and R7e is methyl.
The C1-C6 alkyl group of compounds (7), (8) and (9) is as defined in [1], preferably the alkyl group is C1-C4 alkyl, more preferably the alkyl group is methyl or ethyl and most preferably the alkyl group is methyl.
The C1-C6 alkoxy group of compounds (7), (8) and (9) is as defined in [1], preferably the alkoxy group is C1-C4 alkoxy, more preferably the alkoxy group is methoxy or ethoxy and most preferably the alkoxy group is methoxy.
The halogen atom of compounds (7), (8) and (9) is defined as in [1], preferably the halogen atom is fluorine, chlorine or bromine.
The amino protecting group of compounds (7) and (8) is as defined in [1], preferably the protecting group is t-butoxycarbonyl, benzyl, p-methoxybenzyl, p-bromobenzyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl, more preferably one is t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl, most preferably one is t-butoxycarbonyl.
In compounds (7), (8) and (9), preferably R1e, R2e, R3e and R4e are each independently hydrogen or C1-C4 alkoxy; more preferably R1e, R2e, R3e and R4e are each independently hydrogen or methoxy; most preferably R1e, R2e and R4e are each hydrogen and most preferably R3e is methoxy; and preferably R7e is C1-C4 alkyl, more preferably R7e is C1-C2 alkyl, most preferably R7e is methyl.
In compounds (7) and (8), preferably R8e is hydrogen, t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl; more preferably R8e is hydrogen or t-butoxycarbonyl and most preferably R8e is t-butoxycarbonyl.
The pharmaceutically acceptable salts of compound (9) are as defined in [1].
The processes for the preparation of intermediates [1], [2] and [3] of this invention and the processes [4] and [5] of this invention are described in detail below.
[1] The compound (1) can be prepared according to the following scheme, 
wherein R1a, R2a, R3a, R4a, R5a and R6a are as defined above.
In this step a compound of formula (1) is obtained by the reaction of a compound of formula (10) with a reagent for introducing an amino protecting group in the presence of a base in an inert solvent.
Suitable examples of the reagent for introducing an amino protecting group include halide derivatives or acid anhydrides having amino protecting moieties, for example t-butoxycarbonylhalides such as t-butoxycarbonylchloride and t-butoxycarbonylbromide; di-t-butoxycarbonyldicarbonate; trityl halides such as trityl chloride and trityl bromide; C6-C10 arylmethyl halides, which are optionally substituted with C1-C6 alkyl, C1-C6 alkoxy or halogen, such as benzyl chloride, benzyl bromide, methylbenzyl chloride, methoxybenzyl chloride, methoxybenzyl bromide, bromobenzyl chloride and naphthylmethyl chloride; and C6-C10 arylmethyloxy-carbonylhalides, which are optionally substituted with C1-C6 alkyl, C1-C6 alkoxy or halogen, such as benzyloxycarbonylchloride, benzyloxycarbonylbromide, methylbenzyloxyczarbonylchloride, methoxybenzyloxycarbonylbromide, bromobenzyloxycarbonylchloride and naphthylmethyloxycarbonylchloride. Of these reagents, t-butoxycarbonylhalides, di-t-butoxycarbonyldicarbonate and benzyloxycarbonylhalides which are optionally substituted with methoxy or bromine are preferred, t-Butoxycarbonylchloride, t-butoxycarbonylbromide and di-t-butoxycarbonyldicarbonate are more preferred, and di-t-butoxycarbonyldicarbonate are most preferred.
The examples of the base used in this step include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide, barium hydroxide and magnesium hydroxide; alkali metal alkoxides such as lithium ethoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide; alkai metal or alkaline earth metal hydrides such as lithium hydride, sodium hydride, potassium hydride and calcium hydride; aliphatic amines such as triethylamine, diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); aromatic amines such as pyridine, 4-(N,N-dimethylamino)pyridine, aniline and N,N-dimethylaniline. Aliphatic amines, aromatic amines, alkali metal alkoxides and alkali metal or alkali earth metal hydrides are preferred. Triethylamine, pyridine, 4-(N,N-dimethylamino)pyridine, potassium t-butoxide and sodium hydride are more preferred, and 4-(N,N-dimethylamino)pyridine is most preferred.
The amount of a base used is between 0.01 and 2 equivalents, preferably between 0.02 and 0.1 equivalents.
The solvent employed in this step is not particularly limited provided that it has no adverse effect on the reaction and dissolves the starting materials to at least some extent. Suitable solvents are aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; esters such as methyl acetate, ethyl acetate, methyl propionate and ethyl propionate; nitriles such as acetonitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and mixtures thereof. Aromatic hydrocarbons, halogenated hydrocarbons, ethers, esters, amides and nitriles are preferred. Halogenated hydrocarbons, ethers, esters, amides and nitriles are more preferred, and methylene chloride and ethyl acetate are most preferred.
The reaction temperature employed in this step depends upon various factors such as the nature of the starting materials and the solvent. However, it is usually between xe2x88x9210xc2x0 C. and 100xc2x0 C., and is preferably between 0xc2x0 C. and 50xc2x0 C.
The reaction time employed in this step depends on the reaction temperature and the like. It is typically from 10 minutes to 10 hours, and preferably from 30 minutes to 5 hours.
The desired compound in this step can be isolated from the reaction mixture by a conventional technique, for example, when there is insoluble material in the reaction mixture, the reaction mixture is filtered, the filtrate, if necessary, is neutralized and cooled to afford the desired crystals which are collected by filtration or the solvent of the filtrate is evaporated off and the residue is partitioned between water and an organic solvent immiscible with water, the organic layer is dried over anhydrous magnesium sulfate and concentrated to give the desired product. The desired product thus isolated can be, if necessary, further purified through a conventional technique such as recrystallization or chromatography.
[2] The compound (2) can be prepared according to the following scheme, 
wherein R1b, R2b, R3b, R4b, R7b and R8b are as defined above.
In this step a compound of formula (2) is obtained by the reaction of a compound of formula (11) (hereinafter referred to as compound (11)) with a reducing reagent, capable of reducing a nitro group to an amino group, in an inert solvent.
The reducing agent employed in this step is not particularly limited provided that it can reduce a nitro group into an amino group. A suitable example of the reducing reagent is a combination of hydrogen and a catalyst which is usually used in catalytic reduction. Examples of the catalyst for catalytic reduction include palladium on carbon, palladium black, Raney nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride, and palladium-barium sulfate. Palladium on carbon is preferred.
The pressure of hydrogen employed in this step is not particularly limited, however it is usually between 1 to 10 atmospheres, preferably between 1 and 3 atmospheres.
The solvent employed in this step is not particularly limited provided that it has no adverse effect on the reaction and dissolves the starting materials to at least some extent. Suitable solvents are aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol and butanol; esters such as methyl acetate, ethyl acetate, methyl propionate and ethyl propionate; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and mixtures thereof. Aromatic hydrocarbons, halogenated hydrocarbons, ethers, alcohols, alcohols containing water and amides are preferred. Toluene and methanol are particularly preferred.
The reaction temperature employed in this step depends upon various factors such as the nature of the starting materials, the catalyst and the solvent. However, it is usually between 0xc2x0 C. and 100xc2x0 C., and is preferably between 10xc2x0 C. and 60xc2x0 C.
The reaction time employed in this step depends on the reaction temperature and the like. It is typically from 5 minutes to 24 hours, and preferably from 10 minutes to 10 hours.
The desired compound in this step can be isolated from the reaction mixture by a conventional technique, for example, when there is insoluble material in the reaction mixture, the reaction mixture is filtered, the filtrate, if necessary, is neutralized and cooled to afford the desired crystals which are collected by filtration or the solvent of the filtrate is evaporated off and the residue is partitioned between water and an organic solvent immiscible with water, the organic layer is dried over anhydrous magnesium sulfate and concentrated to give the desired product. The desired product thus isolated can be, if necessary, further purified through a conventional technique such as recrystallization or chromatography.
[3] Compound (3) can be prepared according to step 1 and step 2 described in process [5].
[4] The compound (5) can be prepared using compound (4) as a starting material according to the following scheme, 
wherein R1d, R2d, R3d, R4d, R5d and R6d are as defined above.
In this step a compound of formula (5) is obtained by the reaction of a compound of formula (4) with an alkali metal alkoxide in an inert solvent.
The solvent employed in this step is not particularly limited provided that it has no adverse effect on the reaction and dissolves the starting materials to at least some extent. Suitable solvents are aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol and butanol; esters such as methyl acetate, ethyl acetate, methyl propionate and ethyl propionate; nitrites such as acetonitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and mixtures thereof. Aromatic hydrocarbons, ethers, alcohols, amides, nitrites and mixtures thereof are preferred. Aromatic hydrocarbons, alcohols and mixtures thereof are more preferred. A mixture of toluene and methanol is particularly preferred.
Examples of the alkali metal alkoxide employed in this step include lithium ethoxide, sodium methoxide, sodium ethoxide, sodium t-butoxide and potassium t-butoxide. Sodium methoxide is preferred.
The amount of the alkali metal alkoxide is between 0.1 and 10 equivalents, and preferably between 0.5 and 1 equivalent.
The reaction temperature employed in this step is between xe2x88x9210xc2x0 C. and 100xc2x0 C., and is preferably between 0xc2x0 C. and 50xc2x0 C.
The reaction time employed in this step depends on the reaction temperature and the like. It is usually from 10 minutes to 10 hours, and preferably from 30 minutes to 5 hours.
The desired compound (5) in this step can be isolated from the reaction mixture by a conventional technique, for example, when there is insoluble material in the reaction mixture, the reaction mixture is filtered, the filtrate, if necessary, is neutralized and cooled to afford the desired crystals which are collected by filtration or the solvent of the filtrate is evaporated off and the residue is partitioned between water and an organic solvent immiscible with water, the organic layer is dried over anhydrous magnesium sulfate and concentrated to give the desired product. The desired product thus isolated can be, if necessary, further purified through a conventional technique such as recrystallization or chromatography.
Of the processes for the preparation of compound (5) described above, preferable processes comprise the reaction of compound (4) with lithium ethoxide, sodium methoxide, sodium ethoxide, or potassium t-butoxide in a solvent such as an aromatic hydrocarbon, an alcohol or mixtures thereof, to give compound (5). 
More preferable processes comprise the reaction of compound (4) with sodium methoxide in a mixture of toluene and methanol to give compound (5). 
[5] The compound (9) can be prepared by using compound (6) and compound (7) as starting materials according to the three step reactions shown in the following scheme, 
wherein R1e, R2e, R3e, R4e, R7e and R8e are as defined above.
In this scheme compound (9) is obtained by the condensation of a compound (6) with a compound (7) in the presence of a coupling reagent to afford compound (8) (step 1), if necessary, removal of a protecting group of amino (step 2), followed by cyclization of compound (8) in the presence of an acid (step 3). Procedures of each step are described in detail hereinafter.
Step 1
In this step compound (8) is obtained by condensation of compound (6) with compound (7) in the presence of a coupling reagent and a base in an inert solvent.
The coupling reagent employed in step 1 is not particularly limited provided that it can condense a carboxylic acid with an amine to afford an amide. Examples of the coupling reagent include cyclic anhydrides of C1-C4 alkylphosphonic acid such as cyclic anhydrides of methylphophonic acid, ethylphosphonic acid, propylphosphonic acid and butylphosphonic acid; C1-C4 alkylphosphoryl cyanides such as dimethylphosphoryl cyanide, diethylphosphoryl cyanide and dibutylphosphoryl cyanide; and C6-C10 arylphosphoryl azides such as diphenylphosphoryl azide, ditolylphosphoryl azide and dinaphthylphosphoryl azide. Cyclic anhydrides of C2-C3 alkylphosphonic acids, diethylphosphonic cyanide and diphenylphosphoryl azide are preferred. Cyclic anhydride of propylphosphonic acid is particularly preferred.
The examples of the base used in step 1 include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide, barium hydroxide and magnesium hydroxide; alkali metal alkoxide such as lithium ethoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide; alkali metal or alkaline earth metal hydrides such as lithium hydride, sodium hydride, potassium hydride and calcium hydride; aliphatic amines such as triethylamine, diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); aromatic amines such as pyridine, 4-(N,N-dimethylamino)pyridine, aniline and N,N-dimethylaniline. Aliphatic amines and aromatic amines are preferred. Triethylamine and diisopropylamine are more preferred.
The amount of base used is between 1 and 3 equivalents, preferably between 1.2 and 2 equivalents.
The solvent employed in step 1 is not particularly limited provided that it has no adverse effect on the reaction and dissolves the starting materials to at least some extent. Suitable solvents are aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; esters such as methyl acetate, ethyl acetate, methyl propionate and ethyl propionate; nitriles such as acetonitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and mixtures thereof. Halogenated hydrocarbons, ethers, amides and nitriles are preferred. Halogenated hydrocarbons and nitrites are more preferred, and methylene chloride and acetonitrile are most preferred.
The reaction temperature employed in step 1 is usually between xe2x88x9220xc2x0 C. and 100xc2x0 C., and is preferably between xe2x88x9210xc2x0 C. and 30xc2x0 C.
The reaction time employed in step 1 depends on the reaction temperature and the like. It is typically from 15 minutes to 10 hours, and preferably from 30 minutes to 5 hours.
The desired compound in step 1 can be isolated from the reaction mixture by a conventional technique, for example, the reaction mixture is appropriately neutralized and concentrated and the residue is partitioned between water and an organic solvent immiscible with water, the organic layer is dried over anhydrous magnesium sulfate and concentrated to give the desired product. The desired product thus isolated can be, if necessary, further purified through a conventional technique such as recrystallization or chromatography.
Step 2
In step 2 an amino protecting group of amino in compound (8), if necessary, is removed according to conventional techniques known to those skilled in the art, for example, by using an acid, a base or a reducing agent depending on the type of amino protecting group.
When the amino protecting group is a t-butoxycarbonyl or trityl group, said protecting group can be removed by treating with an acid in an inert solvent.
Examples of the acid employed in the removal of the amino protecting group include inorganic acids such as hydrogen chloride, nitric acid, hydrochloric acid, sulfuric acid and phosphoric acid; organic acids such as acetic acid, trifluoroacetic acid methanesulfonic acid and p-toluenesulfonic acid; Lewis acids such as boron trifluoride; acidic cationic ion-exchange resins such as Dowex 50W (trade mark). Of these acids, inorganic acids and organic acids are preferred. Hydrochloric acid, sulfuric acid, phosphoric acid and trifluoroacetic acid are more preferred, and hydrochloric acid is most preferred.
The solvent employed in step 2 is not particularly limited provided that it has no adverse effect on the reaction and dissolves the starting materials to at least some extent. Suitable solvents are aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol and butanol; esters such as methyl acetate, ethyl acetate, methyl propionate and ethyl propionate; nitrites such as acetonitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and mixtures thereof. Aromatic hydrocarbons, alcohols and esters are preferred. Alcohols and esters are more preferred, and methanol, ethanol and ethyl acetate are particularly preferred.
The reaction temperature employed in step 2 depends upon various factors such as the nature of the starting materials, solvents and acids. However it is usually between 0xc2x0 C. and 150xc2x0 C., and is preferably between 10xc2x0 C. and 100xc2x0 C.
The reaction time employed in step 2 depends on the reaction temperature and the like. It is typically from 5 minutes to 24 hours, and preferably from 10 minutes to 10 hours.
When the amino protecting group of compound (8) is C6-C10 aryl-methyl or C6-C10 aryl-methyloxycarbonyl, both of which may be optionally substituted, said protecting group can be removed by treating with a reducing reagent in an inert solvent (preferably treating with hydrogen in the presence of a catalytic reduction catalyst).
The catalytic reduction catalyst employed in step 2 is not particularly limited provided that it can usually use in catalytic reduction. Examples of the catalyst include palladium on carbon, palladium black, Raney nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride, and palladium-barium sulfate, of which palladium on carbon is preferred.
The solvent employed in step 2 is not particularly limited provided that it has no adverse effect on the reaction and dissolves the starting materials to at least some extent. Suitable solvents are aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol and butanol; esters such as methyl acetate, ethyl acetate, methyl propionate and ethyl propionate; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and mixtures thereof. Aromatic hydrocarbons, ethers, alcohols, alcohols containing water and amides are preferred. Toluene and methanol are particularly preferred.
The pressure of hydrogen employed in step 2 is not particularly limited, however it is usually between 1 and 10 atmospheres, preferably between 1 and 3 atmospheres.
The reaction temperature employed in step 2 depends upon various factors such as the nature of the starting materials, the catalyst and the solvent. However, it is usually between 0xc2x0 C. and 100xc2x0 C., and is preferably between 10xc2x0 C. and 60xc2x0 C.
The reaction time employed in step 2 depends on the reaction temperature and the like. It is typically from 5 minutes to 24 hours, and preferably from 10 minutes to 10 hours.
The desired compound in this step can be isolated from the reaction mixture by a conventional technique, for example, when there is insoluble material in the reaction mixture, the reaction mixture is filtered, the filtrate, if necessary, is neutralized and cooled to afford the desired crystals which are collected by filtration or the solvent of the filtrate is evaporated off and the residue is partitioned between water and an organic solvent immiscible with water, the organic layer is dried over anhydrous magnesium sulfate and concentrated to give the desired product. The desired product thus isolated can be, if necessary, further purified through a conventional technique such as recrystallization or chromatography.
Step 3
In this step compound (9) is obtained by cyclization of a compound (8) (if necessary, a compound from which has been removed an amino protecting group) in the presence of an acid in an inert solvent.
This step can be accomplished by a similar procedure to that described in step 2 which is removal of an amino protecting group such as t-butoxycarbonyl or trityl.
When compound (8), which has an amino protecting group such as t-butoxycarbonyl or trityl, is treated with an acid in step 2, removal of said amino protecting group and cyclization take place at the same time to afford an acid addition salt of compound (9).
Of the processes for the preparation of compound (9) described above, preferable processes comprise the condensation of a compound (6) with a compound (7) in the presence of a coupling reagent such as a cyclic anhydride of C2-C3 alkylphosphonic acid, diethylphosphoryl cyanide or diphenylphosphoryl azide and a base such as an aliphatic amine or aromatic amine in a solvent such as a halogenated hydrocarbon or a nitrile to afford compound (8), followed by removal of the amino protecting group and cyclization of compound (8) in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid to give a benzimidazole compound (9) or a pharmaceutically acceptable salt thereof or followed by removal of the amino protecting group of compound (8) through catalytic hydrogenation in the presence of a catalyst such as palladium on carbon, palladium black, Raney nickel, platinum oxide, triphenylphosphine-rhodium chloride or palladium-barium sulfate in a solvent such as an aromatic hydrocarbon, an ether, an alcohol or an alcohol containing water and by cyclization of the deprotected compound (8) in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid in a solvent such as an alcohol or an ester to give a benzimidazole compound (9) or a pharmaceutically acceptable salt thereof. 
More preferable processes comprise the condensation of a compound (6) with a compound (7) in the presence of the cyclic anhydride of propylphosphonic acid and a base such as triethylamine or diisopropylethylamine in a solvent such as methylene chloride or acetonitrile to afford a compound (8), followed by removal of the amino protecting group and cyclization of compound (8) in the presence of hydrochloric acid to give a benzimidazole compound (9) or a pharmaceutically acceptable salt thereof or followed by removal of the amino protecting group of compound (8) through catalytic hydrogenation in the presence of palladium on carbon in a solvent such as toluene or methanol and by cyclization of the deprotected compound (8) in the presence of hydrochloric acid in a solvent such as methanol, ethanol or ethyl acetate to give a benzimidazole compound (9) or a pharmaceutically acceptable salt thereof. 
Starting materials of [1] to [5] described above are prepared as follows.
Starting materials of formula (10) described in [1] are known compounds or can be prepared by methods known to those skilled in the art (for example Japanese Patent Application Publication Hei 9-295970 or U.S. Pat. No. 5,886,014).
Starting materials of formula (11) described in [2] can be prepared by method A described below using compounds obtained in [4] as starting materials.
Starting materials of formula (4) described in [4] can be prepared by the methods described in [1].
Starting materials of formula (6) described in [5] can be prepared by method B described below. Starting materials of formula (7), wherein R8e is an amino protecting group, can be prepared by the methods described [2] and starting materials of formula (7), wherein R8e is hydrogen, can be prepared by method C described below.
Method A
Compounds of formula (11) are prepared by method A, wherein 
R1b, R2b, R3b, R4b, R7b and R8b are as defined above.
Method A comprises the reaction of a compound of formula (12) with an alkylating reagent in the presence of a base in an inert solvent.
Examples of the alkylating reagent employed in method A include C1-C6 alkyl halides such as methyl iodide, ethyl iodide, propyl iodide, butyl bromide, butyl iodide, pentyl chloride, pentyl iodide, hexyl bromide and hexyl bromide or di-C1-C6 alkyl sulfates such as dimethyl sulfate, diethyl sulfate, dipropyl sulfate, dibutyl sulfate and dihexyl sulfate. Of these alkylating reagents C1-C2 alkyl halides and di-C1-C2 alkyl sulfates are preferred and dimethyl sulfate is particularly preferred.
The amount of the alkylating reagent used in Method A is between 1 and 3 equivalents, preferably between 1.2 and 2 equivalents.
The examples of the base used in method A include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide, barium hydroxide and magnesium hydroxide; alkali metal alkoxides such as lithium ethoxide, sodium methoxide, sodium ethoxide and potassium t-butoxide; alkai metal or alkaline earth metal hydrides such as lithium hydride, sodium hydride, potassium hydride and calcium hydride; aliphatic amines such as triethylamine, diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and aromatic amines such as pyridine, 4-(N,N-dimethylamino)pyridine, aniline and N,N-dimethylaniline. Of these bases, alkali metal alkoxides and alkali metal hydrides are preferred, and potassium t-butoxide and sodium hydride are particularly preferred.
The amount of base used in method A is between 1 and 10 equivalents, preferably between 1.2 and 2 equivalents.
The solvent employed in Method A is not particularly limited provided that it has no adverse effect on the reaction and dissolves the starting materials to at least some extent. Suitable solvents are aliphatic hydrocarbons such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and mixtures thereof. Of these solvents, ethers and amides are preferred and tetrahydrofuran and N,N-dimethylformamide are particularly preferred.
The reaction temperature employed in method A depends upon various factors such as the nature of the starting materials and the solvent. However, it is usually between xe2x88x9220xc2x0 C. and 100xc2x0 C., and is preferably between xe2x88x9210xc2x0 C. and 40xc2x0 C.
The reaction time employed in method A depends on the reaction temperature and the like. However, it is usually from 10 minutes to 10 hours and preferably from 15 minutes to 3 hours.
Method B
Compounds of formula (6) are prepared by method B, wherein 
R9 is C1-C6 alkyl and R10 is hydrogen or an amino protecting group.
Method B comprises, if necessary, the removal of an amino protecting group from compound (13), followed by hydrolysis of the product or compound (13).
The removal reaction of the amino protecting group can be accomplished using similar procedures to those described in step 2.
The hydrolysis can be accomplished using a conventional technique known to those skilled in organic syntheses by using an acid or a base in an inert solvent containing water.
Examples of the acid employed in method B include the same acids as described in step 2, the process of which is the reaction to remove an amino protecting group. Examples of a base employed in method B include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide and alkali metal carbonates such as sodium carbonate and potassium carbonate. Of these bases, sodium hydroxide and potassium hydroxide are preferred.
The inert solvent containing water employed in Method B is not particularly limited provided that it has no adverse effect on the reaction. Suitable inert solvents are aliphatic hydrocarbons such as hexane and cyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; alcohols such as methanol, ethanol, propanol and isopropanol; and carboxylic acids such as acetic acid. Of these solvents, when an acid is used in method B, alcohols and carboxylic acids are preferred and methanol and acetic acid are particularly preferred and when a base is used in method B, alcohols are preferred and methanol is particularly preferred.
The reaction temperature employed in method B depends upon various factors such as the nature of the starting material and the solvent. However, it is usually between xe2x88x9210xc2x0 C. and 150xc2x0 C., and is preferably between 10xc2x0 C. and 100xc2x0 C.
The reaction time employed in method B depends on the reaction temperature and the like. However, it is usually from 5 minutes to 24 hours and preferably from 10 minutes to 10 hours.
In addition, when R9 is t-butyl, the protecting group R9 can be removed using an acid in the same procedure as described in step 2.
Method C
Compounds of formula (7a) wherein R8e is hydrogen are prepared by method C, wherein 
R1e, R2e, R3e, R4e, and R7e are as defined above.
Method C comprises reduction of the nitro group of a compound of formula (14) (which compound is referred to as compound (14) hereinafter). Method C can be accomplished by a similar procedure to the catalytic hydrogenation described in step 2, the process of which is the removal of an amino protecting group.
The desired compounds in method A, B and C can be isolated from the reaction mixture by a conventional technique, for example, when there is insoluble material in the reaction mixture, the reaction mixture is filtered, the filtrate, if necessary, is neutralized and cooled to afford the desired crystals which are collected by filtration or the solvent of the filtrate is evaporated off and the residue is partitioned between water and an organic solvent immiscible with water, the organic layer is dried over anhydrous magnesium sulfate and concentrated to give the desired product. The desired product thus isolated can be, if necessary, further purified through a conventional technique such as recrystallization or chromatography.
Compounds (13) which are starting materials in method B and compounds (14) which are starting materials in method C are known compounds or can be prepared according to a technique known to those skilled in the art (for example Japanese Patent Application Publication Hei 9-295970).